This work plan outlines a research program designed systematically to investigate the relationships between paramagnetic contrast agent (PCA) molecular structure and the ability of these agents to enhance water proton spin relaxation in the context of clinical MRI examinations. A detailed understanding of these structure/function relationships in PCAs containing Gd+3 or Mn+2 will assist in the rational design of new contrast agents with tailored properties; through such an approach we already have helped guide the creation of an advanced agent which currently is undergoing clinical trials. Such information is especially necessary, for PCA design because the properties of any agent are the result of a complex set of interactions involving the paramagnetic material, the molecular structure of the chelate, water, and the biological surroundings. The plan outlined here is based upon a methodological foundation which has been developed over the last five years in our laboratory. This approach includes several complementary magnetic resonance techniques, each of which is designed individually to observe one of the key interactions controlling PCA performance. We utilize multi-frequency electron paramagnetic resonance (EPR at 0.5, 1, 3, 9.5, 35, and 95 GHz), 17O NMR, electron spin echo (ESB), and electron-nuclear double resonance (ENDOR) spectroscopies, as well as nuclear magnetic relaxation dispersion (NMRD) measurements, in this protocol. In order to perform certain experiments, we have constructed one-of-a-kind instruments, like the 95 GHz EPR and the 2 - 4 GHz ESE spectrometers. This suite of instruments is unique in the USA, and it affords us special opportunities to make physical measurements that relate PCA structure to individual factors affecting performance (e.g. water access and organization, tumbling rate, zero field splitting, electron spin relaxation). Also unique in the plan is our collaboration with Schering, AG (Berlin, Germany). Schering organic chemists provide us with a wide variety of special PCAs, often synthesized to our specifications. The collaboration has been extremely successful, providing us at all times with a source of precisely characterized, high-purity agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM042208-06
Application #
2181264
Study Section
Biophysical Chemistry Study Section (BBCB)
Project Start
1990-08-01
Project End
1999-07-31
Budget Start
1995-08-01
Budget End
1996-07-31
Support Year
6
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Kinrade, S D; Schach, A S; Hamilton, R J et al. (2001) NMR evidence of pentaoxo organosilicon complexes in dilute neutral aqueous silicate solutions. Chem Commun (Camb) :1564-5
Knight, C T; Kinrade, S D (1999) Silicon-29 nuclear magnetic resonance spectroscopy detection limits. Anal Chem 71:265-7
Kinrade, S D; Del Nin, J W; Schach, A S et al. (1999) Stable five- and six-coordinated silicate anions in aqueous solution. Science 285:1542-5
Smirnova, T I; Smirnov, A I; Belford, R L et al. (1999) Interaction of Gd(III) MRI contrast agents with membranes: a review of recent EPR studies. MAGMA 8:214-29
Norby, S W; Swartz, H M; Clarkson, R B (1998) Electron and light microscopy studies on particulate EPR spin probes lithium phthalocyanine, fusinite and synthetic chars. J Microsc 192:172-85
Clarkson, R B; Odintsov, B M; Ceroke, P J et al. (1998) Electron paramagnetic resonance and dynamic nuclear polarization of char suspensions: surface science and oximetry. Phys Med Biol 43:1907-20
Smirnova, T I; Smirnov, A I; Belford, R L et al. (1997) Interaction of MRI gadolinium contrast agents with phospholipid bilayers as studied by 95 GHz EPR. Acta Chem Scand 51:562-6
Norby, S W; Weyhenmeyer, J A; Clarkson, R B (1997) Stimulation and inhibition of nitric oxide production in macrophages and neural cells as observed by spin trapping. Free Radic Biol Med 22:1-9
Clarkson, R B; Norby, S W; Smirnov, A et al. (1995) Direct measurement of the accumulation and mitochondrial conversion of nitric oxide within Chinese hamster ovary cells using an intracellular electron paramagnetic resonance technique. Biochim Biophys Acta 1243:496-502
Vahidi, N; Clarkson, R B; Liu, K J et al. (1994) In vivo and in vitro EPR oximetry with fusinite: a new coal-derived, particulate EPR probe. Magn Reson Med 31:139-46

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